ABSTRACT The central goal of this proposal is to explore pathological hallmarks of Alzheimer?s disease (AD) in the retina and evaluate retinal amyloid imaging as a novel approach for diagnosis and monitoring of AD. There is growing evidence that AD affects the neurosensory retina, a developmental outgrowth of the brain and the only CNS tissue directly accessible for high-resolution imaging. The retina exhibits a wide spectrum of pathologies in AD patients, including thinning of the nerve fiber layer, vascular and blood flow changes, and degeneration of retinal ganglion cells (RGCs). The hallmark pathological signs of AD ? amyloid ?-protein (A?) plaques and neurofibrillary tangles (NFT) comprised of hyperphosphorylated tau protein (ptau) ? have long been described in the brain. However, A? deposits in the retina of human AD patients, including early stage cases, were only recently discovered. Further studies have found ptau, A?-like deposits, and elevated A?42 peptides in postmortem AD retinas. Notably, a loss of a subtype of RGCs, melanopsin-containing RGCs, was associated with accumulation of A? inside and around these cells. Preliminary data from our group indicate manifestation of vascular amyloidosis and retinal inflammation (e.g. astrogliosis and microgliosis) surrounding A? fibrils and NFT-like structures, which are specific to the retinas of AD patients. These changes appear to be exacerbated during disease progression. In order to visualize AD pathology, a noninvasive retinal amyloid imaging method has been developed to facilitate repeated monitoring of retinal A? deposits with high resolution and specificity in living transgenic rodent models of AD. Pilot clinical trials implementing this retinal curcumin imaging technology demonstrate its capacity to quantitatively detect retinal A? deposits in living AD patients. Our studies using this retinal amyloid optical imaging in mouse models demonstrate the feasibility to track subtle changes in retinal amyloid plaques during disease progression, and in response to immune-based therapy. Based on the published and preliminary data collected, the following research objectives are proposed: 1) To determine the existence and distribution of amyloid deposits, vascular amyloidosis, intracellular A? oligomers, and tauopathy in the retinas of AD and Mild Cognitive Impairment (MCI) patients; 2) To examine retinal inflammation and degeneration, and evaluate possible correlations with brain pathology and cognitive status in MCI and AD patients, and 3) To noninvasively monitor formation, appearance and clearance of retinal A? deposits in live mouse models of AD, during disease progression and in response to immunotherapy. Results from these studies stand to markedly increase the understanding of how AD affects the retina, and whether retinal amyloid imaging can reliably indicate brain pathology or cognitive status. Given the accessibility of the retina for direct and noninvasive high resolution imaging, targeting this tissue may provide an invaluable approach to identify new biomarkers and screen populations to facilitate prediction of risk, diagnosis and monitoring of AD.